{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:47:33Z","timestamp":1792705653639,"version":"4.5.0"},"reference-count":41,"publisher":"Elsevier BV","issue":"12","license":[{"start":{"date-parts":[[2011,12,1]],"date-time":"2011-12-01T00:00:00Z","timestamp":1322697600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2016,10,7]],"date-time":"2016-10-07T00:00:00Z","timestamp":1475798400000},"content-version":"vor","delay-in-days":1772,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Therapy"],"published-print":{"date-parts":[[2011,12]]},"DOI":"10.1038\/mt.2011.185","type":"journal-article","created":{"date-parts":[[2011,9,27]],"date-time":"2011-09-27T12:03:37Z","timestamp":1317125017000},"page":"2169-2177","source":"Crossref","is-referenced-by-count":74,"title":["Rational Design of Therapeutic siRNAs: Minimizing Off-targeting Potential to Improve the Safety of RNAi Therapy for Huntington's Disease"],"prefix":"10.1016","volume":"19","author":[{"given":"Ryan L","family":"Boudreau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan M","family":"Spengler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly L","family":"Davidson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1038\/mt.2011.185_bib1","doi-asserted-by":"crossref","first-page":"5864","DOI":"10.1093\/emboj\/cdf578","article-title":"Ribonuclease activity and RNA binding of recombinant human Dicer","volume":"21","author":"Provost","year":"2002","journal-title":"EMBO J"},{"key":"10.1038\/mt.2011.185_bib2","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/nrg2843","article-title":"The widespread regulation of microRNA biogenesis, function and decay","volume":"11","author":"Krol","year":"2010","journal-title":"Nat Rev Genet"},{"key":"10.1038\/mt.2011.185_bib3","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nature01957","article-title":"The nuclear RNase III Drosha initiates microRNA processing","volume":"425","author":"Lee","year":"2003","journal-title":"Nature"},{"key":"10.1038\/mt.2011.185_bib4","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/nature03120","article-title":"The Microprocessor complex mediates the genesis of microRNAs","volume":"432","author":"Gregory","year":"2004","journal-title":"Nature"},{"key":"10.1038\/mt.2011.185_bib5","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0092-8674(03)00759-1","article-title":"Asymmetry in the assembly of the RNAi enzyme complex","volume":"115","author":"Schwarz","year":"2003","journal-title":"Cell"},{"key":"10.1038\/mt.2011.185_bib6","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0092-8674(03)00801-8","article-title":"Functional siRNAs and miRNAs exhibit strand bias","volume":"115","author":"Khvorova","year":"2003","journal-title":"Cell"},{"key":"10.1038\/mt.2011.185_bib7","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/nature09267","article-title":"Mammalian microRNAs predominantly act to decrease target mRNA levels","volume":"466","author":"Guo","year":"2010","journal-title":"Nature"},{"key":"10.1038\/mt.2011.185_bib8","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cell.2004.12.035","article-title":"Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets","volume":"120","author":"Lewis","year":"2005","journal-title":"Cell"},{"key":"10.1038\/mt.2011.185_bib9","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nrg2968","article-title":"Current prospects for RNA interference-based therapies","volume":"12","author":"Davidson","year":"2011","journal-title":"Nat Rev Genet"},{"key":"10.1038\/mt.2011.185_bib10","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/nbt0502-505","article-title":"Effective expression of small interfering RNA in human cells","volume":"20","author":"Paul","year":"2002","journal-title":"Nat Biotechnol"},{"key":"10.1038\/mt.2011.185_bib11","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/S1097-2765(02)00541-5","article-title":"Both natural and designed micro RNAs can inhibit the expression of cognate mRNAs when expressed in human cells","volume":"9","author":"Zeng","year":"2002","journal-title":"Mol Cell"},{"key":"10.1038\/mt.2011.185_bib12","doi-asserted-by":"crossref","first-page":"6343","DOI":"10.1073\/pnas.1037853100","article-title":"Genomewide view of gene silencing by small interfering RNAs","volume":"100","author":"Chi","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1038\/mt.2011.185_bib13","doi-asserted-by":"crossref","first-page":"6347","DOI":"10.1073\/pnas.1131959100","article-title":"Specificity of short interfering RNA determined through gene expression signatures","volume":"100","author":"Semizarov","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1038\/mt.2011.185_bib14","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/nbt831","article-title":"Expression profiling reveals off-target gene regulation by RNAi","volume":"21","author":"Jackson","year":"2003","journal-title":"Nat Biotechnol"},{"key":"10.1038\/mt.2011.185_bib15","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/nmeth854","article-title":"3' UTR seed matches, but not overall identity, are associated with RNAi off-targets","volume":"3","author":"Birmingham","year":"2006","journal-title":"Nat Methods"},{"key":"10.1038\/mt.2011.185_bib16","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1261\/rna.28106","article-title":"Off-target effects by siRNA can induce toxic phenotype","volume":"12","author":"Fedorov","year":"2006","journal-title":"RNA"},{"key":"10.1038\/mt.2011.185_bib17","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1261\/rna.704708","article-title":"Experimental validation of the importance of seed complement frequency to siRNA specificity","volume":"14","author":"Anderson","year":"2008","journal-title":"RNA"},{"key":"10.1038\/mt.2011.185_bib18","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1038\/nprot.2007.278","article-title":"A protocol for designing siRNAs with high functionality and specificity","volume":"2","author":"Birmingham","year":"2007","journal-title":"Nat Protoc"},{"key":"10.1038\/mt.2011.185_bib19","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1186\/1471-2105-10-392","article-title":"siDirect 2.0: updated software for designing functional siRNA with reduced seed-dependent off-target effect","volume":"10","author":"Naito","year":"2009","journal-title":"BMC Bioinformatics"},{"key":"10.1038\/mt.2011.185_bib20","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrd3010","article-title":"Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application","volume":"9","author":"Jackson","year":"2010","journal-title":"Nat Rev Drug Discov"},{"key":"10.1038\/mt.2011.185_bib21","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S1474-4422(10)70245-3","article-title":"Huntington's disease: from molecular pathogenesis to clinical treatment","volume":"10","author":"Ross","year":"2011","journal-title":"Lancet Neurol"},{"key":"10.1038\/mt.2011.185_bib22","doi-asserted-by":"crossref","first-page":"5820","DOI":"10.1073\/pnas.0501507102","article-title":"RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model","volume":"102","author":"Harper","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1038\/mt.2011.185_bib23","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.ymthe.2005.05.006","article-title":"Intrastriatal rAAV-mediated delivery of anti-huntingtin shRNAs induces partial reversal of disease progression in R6\/1 Huntington's disease transgenic mice","volume":"12","author":"Rodriguez-Lebron","year":"2005","journal-title":"Mol Ther"},{"key":"10.1038\/mt.2011.185_bib24","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1038\/mt.2008.50","article-title":"AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington's disease","volume":"16","author":"Franich","year":"2008","journal-title":"Mol Ther"},{"key":"10.1038\/mt.2011.185_bib25","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1038\/mt.2009.17","article-title":"Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice","volume":"17","author":"Boudreau","year":"2009","journal-title":"Mol Ther"},{"key":"10.1038\/mt.2011.185_bib26","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/ana.21569","article-title":"Sustained effects of nonallele-specific Huntingtin silencing","volume":"65","author":"Drouet","year":"2009","journal-title":"Ann Neurol"},{"key":"10.1038\/mt.2011.185_bib27","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1261\/rna.1062908","article-title":"Minimizing variables among hairpin-based RNAi vectors reveals the potency of shRNAs","volume":"14","author":"Boudreau","year":"2008","journal-title":"RNA"},{"key":"10.1038\/mt.2011.185_bib28","doi-asserted-by":"crossref","first-page":"5868","DOI":"10.1073\/pnas.0801775105","article-title":"Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi","volume":"105","author":"McBride","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1038\/mt.2011.185_bib29","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/mt.2008.231","article-title":"Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo","volume":"17","author":"Boudreau","year":"2009","journal-title":"Mol Ther"},{"key":"10.1038\/mt.2011.185_bib30","doi-asserted-by":"crossref","first-page":"e63","DOI":"10.1093\/nar\/gkm088","article-title":"Comparison of approaches for rational siRNA design leading to a new efficient and transparent method","volume":"35","author":"Matveeva","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"10.1038\/mt.2011.185_bib31","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1038\/nbt1118","article-title":"Design of a genome-wide siRNA library using an artificial neural network","volume":"23","author":"Huesken","year":"2005","journal-title":"Nat Biotechnol"},{"key":"10.1038\/mt.2011.185_bib32","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.molcel.2007.06.017","article-title":"MicroRNA targeting specificity in mammals: determinants beyond seed pairing","volume":"27","author":"Grimson","year":"2007","journal-title":"Mol Cell"},{"key":"10.1038\/mt.2011.185_bib33","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nature04791","article-title":"Fatality in mice due to oversaturation of cellular microRNA\/short hairpin RNA pathways","volume":"441","author":"Grimm","year":"2006","journal-title":"Nature"},{"key":"10.1038\/mt.2011.185_bib34","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1517\/14728222.12.5.637","article-title":"Small interfering RNA therapy in cancer: mechanism, potential targets, and clinical applications","volume":"12","author":"Huang","year":"2008","journal-title":"Expert Opin Ther Targets"},{"key":"10.1038\/mt.2011.185_bib35","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1261\/rna.1326809","article-title":"MicroRNA-like off-target transcript regulation by siRNAs is species specific","volume":"15","author":"Burchard","year":"2009","journal-title":"RNA"},{"key":"10.1038\/mt.2011.185_bib36","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1261\/rna.30706","article-title":"Position-specific chemical modification of siRNAs reduces \u201coff-target\u201d transcript silencing","volume":"12","author":"Jackson","year":"2006","journal-title":"RNA"},{"key":"10.1038\/mt.2011.185_bib37","doi-asserted-by":"crossref","first-page":"5761","DOI":"10.1093\/nar\/gkq341","article-title":"A screen of chemical modifications identifies position-specific modification by UNA to most potently reduce siRNA off-target effects","volume":"38","author":"Bramsen","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"10.1038\/mt.2011.185_bib38","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1093\/nar\/gkq961","article-title":"Improved specificity of gene silencing by siRNAs containing unlocked nucleobase analogs","volume":"39","author":"Vaish","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"10.1038\/mt.2011.185_bib39","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1089\/10430340260355347","article-title":"Insect cells as a factory to produce adeno-associated virus type 2 vectors","volume":"13","author":"Urabe","year":"2002","journal-title":"Hum Gene Ther"},{"key":"10.1038\/mt.2011.185_bib40","doi-asserted-by":"crossref","first-page":"R183","DOI":"10.1186\/gb-2007-8-9-r183","article-title":"The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists","volume":"8","author":"Huang da","year":"2007","journal-title":"Genome Biol"},{"key":"10.1038\/mt.2011.185_bib41","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1093\/nar\/gkn1064","article-title":"Allegro: analyzing expression and sequence in concert to discover regulatory programs","volume":"37","author":"Halperin","year":"2009","journal-title":"Nucleic Acids Res"}],"container-title":["Molecular Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1525001616327022?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1525001616327022?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2019,6,16]],"date-time":"2019-06-16T11:28:16Z","timestamp":1560684496000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1525001616327022"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,12]]},"references-count":41,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["S1525001616327022"],"URL":"https:\/\/doi.org\/10.1038\/mt.2011.185","relation":{},"ISSN":["1525-0016"],"issn-type":[{"value":"1525-0016","type":"print"}],"subject":[],"published":{"date-parts":[[2011,12]]}}}